ADT and Depression: What Do We Know, What Do We Not Know?

In the last two weeks I’ve had one patient refuse ADT because of his history of depression, another who has been on ADT for 10 months asked me to refer him to a psychiatrist, and another, with CRPC who has been on ADT for 4 years, told me his depression is finally under control. This leaves a lot of issues to confront.

The broad spectrum with which patients react emotionally to losing their testosterone – or don’t, has been of great interest to me for a number of years. The reality is this, after some men go on ADT they face profound changes in mood, energy and libido in particular. On the other hand, some men are fine with it and really have little complaint. And it’s not all about sex.

But let’s focus directly for a moment on the link between ADT and clinically significant Depression – what we might call Major Depression. While there has been a flurry of papers recently, and reasonably well designed studies, that have explored the connection between ADT and cognitive function, few have indicated the proportion of patients who meet criteria for major depression following ADT. 

In point of fact, it may actually go the other way around, as several studies have shown that major depression or depressive symptom burden can alter cognitive function in men. So how much of the cognitive decline that we are seeing with patients on ADT may be attributable to a broader depressive symptomatology is not known. 

It is not uncommon for me to see patients with a history of depression who were diagnosed with prostate cancer after going on supplemental testosterone – which was given to manage their depression. On the other hand, it is not uncommon for me to see a patient who is perfectly well from a mental health perspective prior to ADT, only to need intervention later for a new diagnosis of depression. 

Of course there are all kinds of potential biases here. In the first case, men with depression who are on testosterone are probably more likely to be screened for prostate cancer than those who are not, which may lead to a prostate cancer detection bias. In the second case.  when men go on ADT they get seen more, and I ask about their mood and function, so I might be more likely to diagnose them with an underlying ( ie not caused by the ADT but occurring alongside it) depression. 

There are two hypotheses to consider on this link: One, some men are simply in a ‘pre-depression’ state and the androgen deprivation simply tips them over the edge into a full on depression syndrome; Two, Some men’s mood and mental state is governed to a larger degree by testosterone than others, and depleting that pulls the rug out from under their feet. 

Putting prostate cancer aside for a minute, it is also possible that depression also leads to a lowering of androgen levels, not necessarily the other way around.

I believe I have observed both sides of the story.  So what are the data?

First, consider that the brain is filled with androgen receptors and that they must be there for a reason. So it follows to reason that the deprivation of activity of these androgen receptors may have some medical consequences. 

Second, consider that data from the large studies of cognitive function in men on ADT, of which a few have been published in the last couple of years, do not demonstrate a consistent, reproducible link between ADT and Depression. Yet the instruments used were not specific for the detection of depression

Studies in which men with a pre-existing diagnosis of depression were given therapeutic testosterone to treat the depression have been met with positive, but inconsistent and not-striking results. 

Data from those diagnosed with Post finasteride syndrome ( which I will cover in a later post)  have sought to link depressive symptoms with lowered levels of CNS androgens and steroids in general, but fail to demonstrate a causal link, even if there appears to be guilt by association.

And let’s not forget the fact that these men have cancer too. In fact, as the cancer progresses it can compound the likelihood of psychic distress in patients, which we may misperceive as depression, or even a cognitive decline.

Last week, one of my patients (who’s prognosis is not bad) told me simply that he was “ready to go” and expressed no enthusiasm for the ‘I can make you live forever’ vibe that sometimes I’m afraid we (I) give off in the clinic. Was he depressed or was he, at age 80, just being realistic? His point was that he had had a good life and maybe pursuing quantity of life wasn’t quite as important to him as maintaining quality. Or, maybe he just didn’t think there was too much left to look forward to. At age 35 that would be depression. At 80, is it wrong?

His comment prompted me to probe a little bit. I asked about his family connections, and his social life. Turns out he is living alone and his main interaction on a day is with his beagle…..and his disease isn’t really at a stage where it is ‘ready to take him’. But, beyond what sounds like some isolation and a bit of loneliness, I couldn’t convince he or myself that this was depression. So we’ll continue this conversation in a subsequent visit….

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota

Published Date: March 14th, 2017